1. Field of the Invention
The present invention is a method of manufacturing microstructural components, microparts assemblies and microparts. More particularly, the invention is a method utilizing Metal Matrix Composites Technology and Low Temperature Superconductors Manufacturing Technology for microfabrication.
2. Description of Prior Art
In manufacturing, forming and removing of substantially homogenous materials are the two major or primary processes. The removing process creates a shape by destroying bonds among particles and removing material. Examples include mechanical turning, drilling and grinding, laser machining, electro discharge machining (EDM), chemical etching, traditional carving etc. The forming process creates a shape from a molten substance, solid particles and binder, electroplating solution, etc. utilizing physical changes which occur due to changing temperature, pressure, chemical composition, etc. usually with the help of a mold or pre-form.
IC-based microfabrication technology (methods used to make integrated circuits) covers both removal and forming processes. All existing microfabrication processes remove substantially homogenous materials according to the ‘blueprint’, engineering drawings, idea, intuition, etc. The present invention is a material removing process also.
Nevertheless, in contrast with existing technologies, such removal is not according to a ‘blueprint’. Removal pattern and creation of a shape are based on composition (non-homogeneity) of the metal matrix composite and properties of the selected etching reagent. Each selected reagent has to remove predominantly one component at each given step of the process. The process resembles creation of a landscape by erosion, in other words a ‘blueprint’ is in the composite material by itself.
The invention is suitable as a method of fabrication of an array of solid or hollow microprotrusions, micropins, microneedles etc. Generally speaking, arrays of microparts attached to a base or substrate. The microparts could have micron range dimensions and considerable complexity in design, geometry and materials.
An example of such an array is microneedles (microneedles wafer or disk could have many hundreds of very small solid or hollow needles), which can painlessly penetrate into the skin and enable fluid transfer either into the body as a drug-dispensing device, or from the body to sample interstitial body fluids. More precisely, the microneedles wafer, a medical microdevice component, is an example of microparts assembly or microassembly. Another example is an array of micropunches or micropins attached to a substrate. Micropunches are a tool, which could be utilized to fabricate microstructural components. For example, to perforate plastic, paper, and metal foils on micro-scale. Yet another example is an array of microprotrusions utilized as a special surface insert attached to an orthopedic implant to enhance the connection or bond between tissues and an implant.
Metal Matrix Composites (MMC) Technology
Low temperature multifilamentary superconductors are an example of unidirectional (all elements are elongated in one direction) metal matrix composite. Over 90% of all multifilamentary superconductors are made by extrusion and drawing of sizeable (up to 500 kg) billets made of high purity copper with plurality of longitudinal Nb-46.5% Ti alloy elements spaced apart in a predetermined arrangement. The longitudinal Nb—Ti alloy elements, after being reduced to final size and subjected to several aging heat treatments, become superconducting filaments. Depending on the application, wide range of filament diameters (˜2–100 microns) and filament number (from few dozens to many thousands) are available in commercial superconductors. The Nb—Ti filaments under 15 microns diameter usually have a sub-micron Nb diffusion barrier. Nb3Sn type superconductors have a diffusion barrier separating filament array and copper stabilizer. Filaments usually have strength in the 70–140 KSI range. Etching the matrix off will expose practically unbreakable filaments. For example, taking a thin slice of superconductor having 6000 filaments of 12 microns diameter and etching the matrix off 150 microns deep would create 6000 solid microneedles 12 microns in diameter and 150 microns in height. Microneedles made out of commercial superconductor would be located very close to each other due to the fact that superconductor filaments usually occupy 50–60% of the array cross-section. The medical device microneedles are expected to occupy less than 5% of the array cross-section. Superconductor-like structures made with medically acceptable materials and having sufficient distance between filaments/microneedles would make a good microneedle-precursor composite.
See more details on superconductor manufacturing in Ref. 1, Concise Encyclopedia of Magnetic & Superconducting Materials. Editor, Jan Evetts. 1992. Pergamon Press, Inc., Tarrytown, N.Y. 10591-5153, USA. A chapter: “Multifilamentary Superconducting Composites”, pages 332–338. And some details in depth Ref. 2, Handbook of Metal-forming Processes, by Betzalel Avitzur, 1983, John Wiley & Sons, Inc., 1020 pages. A chapter: “The Production of Multifilament Rod. The State of the Art—Superconducting Wire”, pages 429–432.
Brothers John and Peter Roberts made the first extruded metal matrix composite superconductor. See U.S. Pat. No. 3,625,662 “Superconductor” by Roberts, et al. (Dec. 7, 1971, Brunswick Corp.). This patent teaches the use of extrusion and drawing to fabricate a composite having superconductor filaments embedded in a matrix, which is a non-superconductor. Roberts's wire samples had filaments as small as 0.625 microns. Later those types of structures were named Multifilamentary Superconductors to differentiate them from the tape superconductors. U.S. Pat. No. 5,127,149 “Method of production for multifilament niobium-tin superconductors” by Ozeryansky, (Jul. 7, 1992, Intermagnetics General Corp.) teaches the use of extrusion and drawing to fabricate an assembly incorporating complex shapes and combination of materials with extremely poor matching of properties.
Another metal matrix composite example is stainless steel filaments in mild steel matrix. In U.S. Pat. No. 3,379,000 (Apr. 23, 1968) “Metal Filaments Suitable for Textiles” by Weber et al. MMC technology is utilized for manufacturing high quality stainless steel fibers. Billets were constricted by extrusion and brought to final size by cold drawing. Low carbon steel matrix was etched off in-line exposing the bundle of fibers. In the 1970's Brunswick Corporation manufactured high quality metal fibers utilizing MMC technology. Roberts brothers also applied MMC technology to fabricate micro-structural components. For example, U.S. Pat. No. 3,506,885 “Electric Device Having Passage Structure Electrode”, by Roberts, et al. (Apr. 14, 1970) and U.S. Pat. No. 3,868,792 also by Roberts, et al. (Mar. 4, 1975). Extrusion and drawing was utilized to fabricate “collimated hole structure” or a “passage structure” (structure having plurality of micro-orifices) suggested for electrolytic capacitors and as a tip (structure having multiplicity of small nozzles) for a drilling device.
Potential uses of MMC technology to fabricate unique microstructural components were first recognized in the early 1950's. See U.S. Pat. No. 2,499,977 (Mar. 7, 1950) “Method of Forming Gridlike Structure” for high frequency electric discharge devices by W. J. Scott. The method comprises assembling into a bundle a plurality of rods, which have been coated with a metal, of which the grid has to be formed. Surrounding the bundle with a tube and reducing the cross sectional area of the bundle-in-the-tube by drawing. After the bundle has been reduced to final size and cut in sections the core rods are removed by a suitable chemical reagent, which does not attack the grid material. U.S. Pat. No. 2.628,417(Feb. 17, 1953) “Method of Preparing Perforate Bodies” disclosing a method of fabricating of very small orifices by Ivan Peyches. A particular example is making a spinneret (a disk with a plurality of very small orifices) for manufacturing of synthetic fibers. Peyches suggests using a drilled billet with holes filled with glass, extruding said billet to the designated diameter, slicing the material to form thin sections and leaching out the glass cores from those sections.
Microneedles Medical Devices
Skin is a protective multi-layer barrier between the body and environment. At approximately 200 microns thick, the epidermis is the outermost layer of skin and it contains many of the components that give skin it unique barrier-protective characteristics. The outermost layer of epidermis, the stratum corneum, which is about 15 microns thick when dry and about 50 microns when fully hydrated, acts as a barrier for an extremely large variety of compounds. The stratum corneum is a heterogeneous layer of flattened, relatively dry, keratinised cells with a dense underlying layer commonly called the “horny layer” is both tough and flexible, with a significant degree of elasticity. These characteristics make the stratum corneum unique and an effective barrier, resistant to penetration. Beneath the epidermis is the dermis, which houses blood vessels and nerve endings. Millions of small capillaries feed the upper levels of the dermis. These capillaries extend to just above of the nerve endings that also are located in the dermis.
Drugs are commonly administered orally, however, many drugs cannot be effectively delivered in this manner, due to their degradation in gastrointestinal tract and possible elimination by the liver. Furthermore, some drugs cannot effectively diffuse across the intestinal mucosa. The use of needles is another well-developed and widespread technique for delivering drugs across biological barriers. While effective for this purpose, needles are cumbersome; generally cause pain, damage to skin at the site of insertion, bleeding, risk of infection and disease transmission. Similarly, current methods of sampling biological fluids are invasive and bear the same disadvantages. Needle technique also is not convenient for the long-term, controlled continuous drug delivery. Current topical drug delivery methods are based upon use of penetration enhancing methods, which often cause skin irritation, and the use of occlusive patches that hydrate the stratum corneum to reduce its barrier properties. Only small fractions of topically applied drugs penetrate skin, usually with very poor efficiency.
Responding to the long felt need existed in medical art Martin Gerstel, et al. had disclosed the feasible alternative to drug delivery by injection in U.S. Pat. No. 3,964,482 (1976). The disclosed device designated for “administering a drug comprising a plurality of projections, a drug reservoir containing a drug, and were the projections extend from the reservoir and are adapted for penetrating the stratum corneum for percutaneously administering a drug from the reservoir to produce a local or systematic physiological or pharmacological effect.” An array of either solid or hollow microneedles is used to penetrate through the stratum corneum, into the epidermal layer, but not to the dermal layer. Fluid is to be dispensed either through hollow microneedles, through permeable solid projections, or around non-permeable solid projections that are surrounded by a permeable material or an orifice. The microneedle size is disclosed as having a diameter of ˜125 to 1700 microns, and a length in the range of 5–100 microns.
According to Gerstel the term “percutaneous” means penetration through the skin “to the local or systemic circulatory system by puncturing, scraping, or cutting the stratum corneum” but not penetrating “to substantial extent the interior layers of skin.” Once a drug penetrates through the stratum corneum, with the aid of a microneedle drug delivery device, penetration through the remaining layers of the skin proceeds readily. Having microneedle heights chosen to avoid the nerve endings, which are up to 100 microns deep, drug injections will be painless.
The ˜125 microns diameter needles were the smallest needles available in the 1970's. If Gerstel had available good, strong and reasonably priced arrays of hollow microneedles, one could imagine, his drug delivery device would improve quality of life for millions people. Even today, more than twenty years later, microneedles devices still are not available to the public.
Another structure, disclosed in U.S. Pat. No. 6,083,196 by Trautman et al. (Jul. 4, 2000) and U.S. Pat. No. 6,219,574 by Cormier et al. (Apr. 17, 2001, both ALZA Corp.) for a device, which enhances transdermal agent delivery and sampling. It employs a plurality of solid metallic microblades, etched and mechanically bent from thin (˜100 micron thick) titanium sheet. U.S. Pat. No. 6,050,988 by Zuck (Apr. 18, 2000), also ALZA Corp., disclosed a structure made of thin metal sheet with microblades that do not require bending. Zuck utilizes assemblies of rather high complexity in his device.
Microfabrication
Much research has been directed towards the development of microneedles utilizing micro-fabrication techniques. These microfabrication processes are based on well-developed methods used to make integrated circuits (IC-technology) and other microelectronic devices. The approach promises the possibility of producing numerous, small needles, which are sufficient to penetrate stratum corneum. There are a number of patents granted and pending; utilizing one or more microfabrication processes. Those processes, for example, are described in depth in: Ref.3, Fundamentals of Microfabrication by Madou, Mark J. CRC Press, LLC 1997, 589 pgs. See Table of Content and pages 328–335.
For example, U.S. Pat. No. 6,334,856 to Allen et al. (Jan. 1, 2002, Georgia Tech) discloses several microfabrication methods of making microneedles. A preferred method of fabricating hollow metal microneedles utilizes the micromold electroplating techniques. First electroplating the micromold forms an array of hollow microneedles, then the micromold is removed from the microneedle array. The Georgia Tech patent also discloses fabrication of arrays of microneedles utilizing several micromachining methods, and plastic microneedles by injection micromolding technique. Another example, U.S. Pat. No. 6,331,266 (by Powel, et al. Dec. 18, 2001) and U.S. Pat. No. 6,471,903 (by Sherman, et al. Oct. 29, 2002), in which plastic microneedles are micro-molded by injection molding, and compression molding or embossing. In U.S. Pat. No. 6,533,949 (by Yeshurun, et al. Mar. 18, 2003) hollow microneedles are processed by improved micromachining methods.
Microfabrication is well developed and highly diversified technology. The microfabrication methods for the manufacture of microneedles have exhibited a lot of progress in recent years. Nevertheless, those methods are generally time consuming, expensive and the mechanical properties of the microfabricated microneedles are far less than what is considered mandatory for stainless steel hypodermic needles.
IC technology can't utilize cold work texture essential to achieve combination of strength, hardness and ductility required for hypodermic needles. Hypothetical example, microneedles are micromachined from a high strength yet still substantially ductile titanium alloy substrate. Cold work, more precisely cold rolling, is the most efficient way to fabricate 300–400 microns thick titanium sheet. The high strength is mainly the result of cold work texture, in this example it is a cold rolling texture, specifically texture developed in direction of rolling or longitudinal direction. Titanium microneedles micromachined from such substrate will have high strength texture in transverse (wrong) direction. Transverse texture will make microneedles predisposed to fracturing. The matter of fact, any elongated element having transverse texture is highly predisposed to fracturing.
One shortcoming of microneedles made by micromachining techniques is the brittleness of the resulting microneedles. Microneedles made from silicon or silicon oxide are highly brittle. As a result, a significant proportion of the microneedles may fracture from stress during penetration, leaving needle fragments within the tissue. Microneedles made by electroplating are not as brittle as those made of silicone or silicon oxide, nevertheless, electroplated structures do not have the combination of strength and ductility desirable for hypodermic needles. Plastic needles do not have the strength and hardness to hold “the edge”, which is critical for performance of hollow needles having thin wall sections.
Microfabrication requires sophisticated and expensive equipment and a highly trained workforce. Packaging or assembling of microparts is always a difficult and costly operation, which also requires complex equipment. Packaging expenses frequently exceed the cost of fabricating a micro part. Accordingly, a continuing need exists in the industry for an improved method for the manufacture of microneedles.